This invention relates generally to the field of drug delivery. More particularly, this invention relates to a non-invasive method of increasing the permeability of skin and other membranes through ultrasound or a combination of ultrasound and chemical enhancers for selectively enhancing transdermal and/or transmucosal drug delivery into the body.
The stratum corneum is chiefly responsible for the well known barrier properties of skin. Thus, it is this layer that presents the greatest barrier to transdermal flux of drugs or other molecules into the body. The stratum corneum, the outer horny layer of the skin, is a complex structure of compact keratinized cell remnants separated by lipid domains. Compared to the oral or gastric mucosa, the stratum corneum is much less permeable to molecules either external or internal to the body. The stratum corneum is formed from keratinocytes, which comprise the majority of epidermis cells, that lose their nuclei and become corneocytes. These dead cells then form the stratum corneum, which has a thickness of only about 10-20 .mu.m and, as noted above, is a very resistant waterproof membrane that protects the body from invasion by exterior substances and the outward migration of fluids and dissolved molecules. The stratum corneum is continuously renewed by shedding of corneum cells during desquamination and the formation of new corneum cells by the keratinization process.
The flux of a drug or analyte across the skin can be increased by changing either the resistance (the diffusion coefficient) or the driving force (the gradient for diffusion). Flux may be enhanced by the use of so-called penetration or chemical enhancers. Chemical enhancers are well known in the art and a more detailed description will follow.
Other methods of increasing the permeability of skin to drugs have been described, such as ultrasound or iontophoresis. Iontophoresis involves the application of an external electric field and topical delivery of an ionized form of drug or an unionized drug carried with the water flux associated with ion transport (electro-osmosis). While permeation enhancement with iontophoresis has been effective, control of drug delivery and irreversible skin damage are problems associated with the technique.
Ultrasound has also been used to enhance permeability of the skin and synthetic membranes to drugs and other molecules. Ultrasound has been defined as mechanical pressure waves with frequencies above 20 kHz, H. Lutz et al., Manual Of Ultrasound 3-12 (1984). Ultrasound is generated by vibrating a piezoelectric crystal or other electromechanical element by passing an alternating current through the material, R. Brucks et al., 6 Pharm. Res. 697 (1989). The use of ultrasound to increase the permeability of the skin to drug molecules has been termed sonophoresis or phonophoresis.
U.S. Pat. No. 4,309,989 to Fahim describes topical application of medications in a coupling agent for the treatment of Herpes virus infections and demidox mite infestations. The medications are massaged into the affected area concurrently with application of ultrasound to cause the medication to penetrate the skin. U.S. Pat. No. 4,372,296 to Fahim similarly describes treatment of acnes by topical application of zinc sulfate and ascorbic acid in a coupling agent.
U.S. Pat. No. 4,767,402 to Kost et al. discloses a method for enhancing and controlling infusion of molecules having a low rate of permeability through skin using ultrasound in the frequency range of between 20 kHz and 10 MHz, and in the intensity range of between 0 and 3 W/cm.sub.2. The molecules are either incorporated in a coupling agent or, alternatively, applied through a transdermal patch. Kost et al. further teach that the parameters of time, frequency, and power can be optimized to suit individual situations and differences in permeability of various molecules and of various skins. U.S. Pat. No. 4,780,212 to Kost et al. teaches use time, intensity, and frequency control to regulate the permeability of molecules through polymer and biological membranes. Further, the choice of solvents and media containing the molecules also affects permeation of the molecules through the membranes. Transbuccal drug delivery with ultrasound has also been disclosed, U.S. Pat. No. 4,948,587 to Kost et al.
U.S. Pat. No. 5,115,805 to Bommannan et al. discloses the use of specific frequencies of ultrasound to enhance the rate of permeation of drugs through human skin. Frequencies above 10 MHz gave improved penetration of the skin above that described earlier. It is alleged but not shown that chemical penetration enhancers and/or iontophoresis could be used in connection with the ultrasound treatment.
U.S. Pat. No. 5,016,615 to Driller et al. involves local application of a medication by implanting a drug-containing receptacle adjacent to a body tissue to be treated and then applying ultrasound to drive the drug out of the receptacle and into the body tissue. This method has the disadvantage of requiring surgical implantation of the drug receptacle and a noninvasive technique is preferred. U.S. Pat. No. 4,821,740 to Tachibana et al. discloses a kit for providing external medicines that includes a drug-containing layer and an ultrasonic oscillator for releasing the drugs for uptake through the surface of the skin. In U.S. Pat. No. 5,007,438 to Tachibana et al. is described an application kit in which a layer of medication and an ultrasound transducer are disposed within an enclosure. The transducer may be battery powered. Ultrasound causes the medication to move from the device to the skin and then the ultrasound energy can be varied to control the rate of administration through the skin.
Other references teaching use of ultrasound to deliver drugs through the skin include D. Bommannan et al., 9 Pharmaceutical Res. 559 (1992); D. Bommannan et al., 9 Pharmaceutical Res. 1043 (1992); K. Tachibana, 9 Pharmaceutical Res. 952 (1992); P. Tyle & P. Agrawala, 6 Pharmaceutical Res. 355 (1989); H. Benson et al., 8 Pharmaceutical Res. 1991); Do Levy et al., 83 J. Clin. Invest. 2074 (1989).
Permeation through the stratum corneum can occur by (a) intracellular penetration, (b) intercellular penetration, and (c) transappendageal penetration, especially through the sebaceous pathway of the pilosebaceous apparatus and the aqueous pathway of the salty sweat glands. The utility of ultrasound in enhancing the permeability of the stratum corneum and, consequently, increasing transdermal flux rate is thought to derive from thermal and mechanical alteration of biological tissues. The parameters of ultrasound that are manipulable to improve or control penetration include frequency, intensity, and time of exposure. All three of these parameters may be modulated simultaneously in a complex fashion to increase the effect or efficiency of the ultrasound as it relates to enhancing the transdermal molecular flux rate either into or out of the human body. Other factors also play a part, for example the composition and structure of the membrane through which molecules are to be transported, the physical and chemical characteristics of the medium in which the molecules are suspended, and the nature of the molecules themselves. Since ultrasound is rapidly attenuated in air, a coupling agent, preferably one having lowest realizable absorption coefficient that is non-staining, nonirritating, and slow drying, may be needed to efficiently transfer the ultrasonic energy from the ultrasound transducer into the skin. When a chemical enhancer fluid or anti-irritant or both are employed, they may function as the coupling agent. For example, glycerin used as an anti-irritant may also function as a coupling agent. If needed, additional components may be added to the enhancer fluid to increase the efficiency of ultrasonic transduction. In general, ultrasound exposure times for permeation through human skin have been less than 60 minutes, preferably less than 10 minutes. It has been suggested that the maximum limit of exposure should be determined by monitoring skin temperature. However, monitoring of skin surface temperature would not necessarily monitor events such as rupture of cell membranes by mechanical shear forces which could occur at low temperatures with short duration, high intensity ultrasound. The exposure may be either continuous or pulsed to reduce heating of biological membranes. Average intensities have been in the range of 0.01-5 W/cm.sup.2 and are selected to be high enough to achieve the desired result and low enough to avoid significant elevation of skin temperature. Frequencies have varied from 20 kHz to 50 MHz, preferably 5-30 MHz. The depth of penetration of ultrasonic energy into living soft tissue is inversely proportional to the frequency, thus high frequencies have been suggested to improve drug penetration through the skin by concentrating the effect in the outermost skin layer, the stratum corneum. Various refractive and/or reflective ultrasonic focusing systems may also be employed to concentrate the ultrasonic energy in the desired tissue independent of the fundamental frequency. When appropriate phase conditions are met, resonance of the system can be induced to favor higher frequency harmonic components of the fundamental ultrasonic energy, causing local zones of ultrasonic energy at 2, 3, 4 or more times the fundamental frequency.
Thus, while the use of ultrasound for drug delivery is known, results have been largely disappointing in that enhancement of permeability has been relatively low. There is no consensus on the efficacy of ultrasound for increasing drug flux across the skin. While some studies report the success of sonophoresis, J. Davick et al., 68 Phys. Ther. 1672 (1988); J. Griffin et al., 47 Phys. Ther. 594 (1967); J. Griffin & J. Touchstone, 42 Am. J. Phys. Med. 77 (1963); J. Griffin et al., 44 Am. J. Phys. Med. 20 (1965); D. Levy et al., 83 J. Clin. Invest. 2074); D. Bommannan et al., 9 Pharm. Res. 559 (1992), others have obtained negative results, H. Benson et al., 69 Phys. Ther. 113 (1988); J. McElnay et al., 20 Br. J, Clin. Pharmacol. 4221 (1985); H. Pratzel et al., 13 J. Rheumatol. 1122 (1986). Systems in which rodent skin were employed showed the most promising results, whereas systems in which human skin was employed have generally shown disappointing results. It is well known to those skilled in the art that rodent skin is much more permeable than human skin, and consequently the above results do not teach one skilled in the art how to effectively utilize sonophoresis as applied to transdermal delivery and/or monitoring through human skin.
In view of the foregoing problems and/or deficiencies, the development of a method for safely enhancing the permeability of the skin for transdermal delivery of drugs to a greater extent than can be achieved passively, and/or providing greater control over delivery rates and/or timing would be a significant advancement in the art.
Tattoos for both surgical and general use have traditionally been applied with one or more needles mounted in instruments or pens that may be hand held for dipping of the exposed needles in an appropriate solution containing pigment. Then the needles are used to puncture the skin so that the pigment is deposited subdermally. One improvement, described in U.S. Pat. No. 4,798,582 to Sarath et al., provided continuous delivery of pigment solution from a storage cartridge. Representative examples of electrical tattooing machines include U.S. Pat. Nos. 4,644,952; 4,508,106; 4,204,438; 4,159,659; and 4,031,783.